SAMe: – The Multi-Functional Supernutrient

SAMe: – The Multi-Functional Supernutrient

By Ward Dean, M.D.

For more than 25 years S-adenosyl methionine (SAMe) has been prescribed by doctors in Europe as a treatment for depression, osteoarthritis, liver
disease, schizophrenia, demyelinating diseases (like multiple sclerosis), dementia, peripheral neuropathy, Attention Deficit Disorder (ADD), migraine headaches, cardiovascular disease and other conditions. Only in the last several years has it been available in America as a dietary supplement. SAMe is a metabolite of the essential amino acid methionine in combination with the universal energy molecule adenosine-triphosphate (ATP). SAMe is found in every cell of the body.

Anti–aging nutrient factor

A healthy young body manufactures all the SAMe it needs from the amino acids betaine and methionine. However, with age, the body is apparently less able to produce adequate SAMe. Levels of SAMe decline due to aging and other causes. For example, a deficiency of methionine, vitamin B12, or folic acid can result in decreased SAMe synthesis. This may contribute to the development of arthritis, depression and dementia in the elderly. Fortunately, these disturbances can often be mitigated by restoring SAMe to more youthful levels with a SAMe supplement. For maximum effectiveness SAMe should be taken with vitamin B12 and folate (folic acid), which can be obtained in adequate amounts in almost any well-formulated multi-nutrient supplement.

SAMe and Depression:

Clinical Effectiveness and Mechanisms of Action

SAMe is used in the formation of neurotransmitters, phospholipids (like phosphatidylcholine and phosphatidylserine) and the pineal hormone melatonin. SAMe also has a beneficial effect on neuronal membranes. It increases the fluidity of cell membranes and improves neurotransmission by increasing the number of available neurotransmitter receptors. Finally, SAMe improves binding of neurotransmitters to receptor sites, which results in increased serotonin and dopamine activity.
Significantly, research has shown that one of the ways that tricyclic antidepressant drugs work is by raising the body’s level of SAMe.

SAMe has been proven to be effective in the relief of all forms of depression except manic depressive illness. SAMe is particularly good for the types of depression that have no apparent cause. More than 100 published studies have demonstrated the anti-depressive actions of SAMe. A meta-analysis of seven double-blind studies demonstrated that SAMe is dramatically more effective than a placebo (74% compared to 5%). Analyses of nine double-blinded clinical studies have confirmed that SAMe is 15% more effective as a treatment for depression than tricyclic anti-depressant drugs (76 % compared to 61%).

While SAMe is more rapid-acting than antidepressant drugs, it is completely devoid of prescription antidepressants side effects like constipation, agitation, insomnia, and sexual dysfunction. Because SAMe is so fast-acting, it is especially valuable when a rapid recovery is essential, as with those who may be suicidal. SAMe may be useful as well in treating other illnesses currently treated with antidepressants such as panic disorder, agoraphobia, bulimia, chronic pain syndromes, post-traumatic stress
disorder, and attention deficit disorder.

The results of studies from Great Britain, Italy, and the United States indicate that SAMe is an especially useful antidepressant for people who cannot tolerate the side  effects of prescription antidepressants. Depressed patients who can especially benefit from SAMe are the elderly and those who suffer from cardiac arrhythmias, seizure disorders, glaucoma, hypotension, constipation, or a recent heart attack.

Say good-bye to postpartum blues

In addition to its generalized anti-depressant actions, SAMe produces significant effects on postpartum (after pregnancy) depression and the depression that occurs from drug withdrawal. SAMe’s benefits in these conditions probably occur from its combined beneficial effect on brain and liver function. In one study on women with postpartum depression, the administration of SAMe produced significantly better mood scores than placebo. In another study of opiate drug abusers, SAMe significantly reduced the psychological distress, anxiety and depression that occurred during drug detoxification and rehabilitation.

SAMe and Osteoarthritis

Osteoarthritis is the localized degeneration of joint cartilage. It affects mainly the weight-bearing joints and is more common in the elderly. Obesity, mechanical stress of repetitive movements, and major trauma such as sports injuries are contributing factors towards its development. Osteoarthritis causes achy pain in the joints, limitations of movement and range of motion, and loss of dexterity. Symptoms of osteoarthritis generally begin in middle age, and by age 60, most people have some degree of osteoarthritis. Consequently, osteoarthritis may be considered a wear-and-tear disease of aging.

Osteoarthritis is caused by a breakdown in cellular processes that produce, maintain and repair cartilage. A layer of connective tissue that surrounds joints is called synovium. Synovium secretes a viscous fluid that acts as a lubricant. Cartilage contains specialized cells called chondrocytes. Chondrocytes manufacture proteins known as proteoglycans that consist of chondroitin and keratin sulfate molecules that are strung on core proteins. The proteoglycans hold water in the joint and, in conjunction with the joint cartilage, serve as a shock absorber.

Physical stress on joints causes destruction of proteoglycans and collagen, and may also inhibit the production of these substances by chondrocytes. When the chondrocytes are unable to make enough proteoglycans and when there is excessive destruction of the proteoglycans and the collagen matrix (known as glycosaminoglycans), the joint starts to erode. This is how osteoarthritis starts.

Joint-destroying anti-arthritic drugs

Modern medicine treats osteoarthritis with three types of drugs: (1) pain relievers like salicylates; (2) nonsteroidal anti-inflammatory drugs (NSAIDs); and (3) steroidal anti-inflammatory drugs. In addition to producing side effects, virtually all drugs that are used to treat osteoarthritis have destructive effects on the articular cartilage lining the bones that form a joint. Each class of drug contributes to joint destruction by a different mechanism.

NSAIDs suppress proteoglycan synthesis by the chondrocyte. The depletion of proteoglycans leaves the chondrocytes more vulnerable to further damage and causes cascading effects that accelerate the degeneration of cartilage. The NSAID-related damage to chondrocyte metabolism is more profound in osteoarthritic cartilage than in normal cartilage. In addition, NSAIDs may cause abdominal pain by irritating the stomach lining, which may progress to gastritis and stomach bleeding. They also interfere with platelet function and the blood’s ability to clot.

Analgesics like salicylates inhibit the enzymes involved in the early stages of chondroitin sulfate biosynthesis. If taken too frequently, salicylates can cause gastric pain and bleeding. The exception is copper salicylate, which does not damage the gut. Acetaminophen (Tylenol™) does not reduce inflammation like aspirin, and can cause liver or kidney damage in chronic or high dosages.

Diagram of Joint Structure
a and b, articular ends of two bones with articular cartilages; p, peristeum; s, synovial layer, and f, fibrous layer of the articular capsule; c, articular cavity.

Steroids are effective at reducing inflammation, but produce significant damage to chondrocytes. A study compared the effects of the NSAID indomethacin and the steroid dexamethasone on chondrocytes. The NSAID group resulted in three times as many dead chondrocyte cells as the control group. The steroid group had four times the number of dead cells. In addition, the long-term effect of corticosteroids can result in a condition which mimics Cushing’s Syndrome, with a number of adverse age-accelerating effects.

Regenerate cartilage in arthritic joints

A more logical (and more beneficial) approach to treating osteoarthritis is to use substances which have chrondro-protective and chondro-regenerative effects. Such substances can reduce joint pain and inflammation without harming the joint like the above-mentioned classes of drugs, and they actually relieve osteoarthritis by re-growing joint cartilage. Two of the most promising joint protecting-and-repairing substances are glucosamine (sulfate and hydrochloride) and SAMe.

SAMe protects and repairs joints by (1) increasing the number of chondrocytes (cartilage cells), (2) stimulating the synthesis of proteoglycans by articular chondrocytes, and (3) decreasing cartilage loss. SAMe protects synovial cells against destruction by tumor necrosing factor (TNF), and blocks enzymes that degrade cartilage. SAMe also relieves pain and inflammation. Studies conducted over the last two decades in Europe and the United States have demonstrated the extraordinary clinical benefits of SAMe. More than 21,000 patients with osteoarthritis have been treated with SAMe in detailed clinical trials, with improvement reported by almost 80%.

Effective as and better tolerated than NSAIDs

In double-blind trials, SAMe use resulted in reduced pain scores and alleviated the symptoms of arthritic patients as effectively as the NSAIDs ibuprofen (Advil, Motrin, Nuprin, etc.), indomethacin, naproxen, and piroxicam. The bottom line in all of these studies is that SAMe has significant advantages over NSAIDs. NSAIDs are associated with significant risk of toxicity, side effects and actually promote the joint-destroying disease process of osteoarthritis. By contrast, SAMe may actually reverse the disease process of osteoarthritis without risk or side effects. Clearly, SAMe is an innovative alternative to the drugs currently used in the treatment of osteoarthritis.

SAMe and Liver Disease

The most dramatic benefits of SAMe may be in the liver. SAMe can single-handedly cause the liver to regenerate. SAMe actually repairs or reverses damage to the liver caused by cirrhosis. In fact, the liver contains special SAMe enzymes for regenerating liver tissue. SAMe is a key metabolite in liver biochemistry and performs two crucial functions. It methylates, and forms the livers most vital substance, the antioxidant and detoxicant amino acid glutathione. The liver is the primary chemical filter in the body. It detoxifies every chemical the body encounters, including drugs and toxins by transforming them into non-toxic metabolites. The liver also makes bile, and creates other substances such as lipoproteins. Unfortunately, liver tissue can be destroyed by chemicals, pollutants and drugs. Fortunately, the liver has a high capacity to regenerate. Up to 80% of the liver can be surgically removed, and it will grow back to normal size in about three months.

However, the liver is not invincible. Toxins can create enough structural damage and blockages that cause increasing levels of liver damage. Cirrhosis is a fibrotic process which results in a slow liver death. Cirrhosis starts with fatty infiltrations and progresses until the organ is filled with scar tissue and loses its ability to perform its primary functions. Human studies have shown that giving SAMe to patients with cirrhosis restores bile function and increases bile salts. Other studies have shown that SAMe increases glutathione levels and restores the detoxification processes in patients with liver damage. For example, acetaminophen (Tylenol) is extremely toxic to the liver. In a mouse study, impending deaths from high doses of acetaminophen can be completely abolished if SAMe is given within one hour. Individuals with livers damaged by alcohol, toxins and diseases such as hepatitis have a higher risk for developing liver cancer. SAMe has been shown to reduce the risk of liver cancer.

SAMe and Heart Disease

Homocysteine is a metabolite of methionine that damages the cells that line the arteries. Damage to these cells leads to atherosclerosis. Elevated levels of homocysteine are becoming increasingly recognized as a major risk factor for heart attacks. SAMe plays an important role in neutralizing homocysteine. Researchers found that high levels of homocysteine correlate with an enzyme (5-methyltetrahydrofolate) that converts folate into its active form. SAMe prevents the breakdown of this enzyme, which turns homocysteine back into methionine. They also found a clear correlation between high homocysteine levels, low SAMe levels and heart disease. It’s apparent that SAMe is important for a healthy cardiovascular system.

SAMe and Fibromyalgia

Fibromyalgia is a systemic disorder that causes chronic, deep musculoskeletal pain at different anatomic sites. Other symptoms of fibromyalgia include sleep disturbances, overwhelming fatigue and joint swelling. Fibromyalgia affects about two percent of the population (mostly women) and shares many common features with chronic fatigue syndrome. The only difference in their diagnostic criteria is the requirement for musculoskeletal pain in fibromyalgia, and fatigue in chronic fatigue syndrome.
Because fibromyalgia is often treated with antidepressants, scientists tried using SAMe as a substitute treatment. They discovered that SAMe reduced the number of pain trigger points, reduced fatigue, reduced morning stiffness and improved the mood in fibromyalgia patients. One double-blind crossover study of 17 patients with fibromyalgia found that patients who were injected with SAMe for 21 days demonstrated significant reduction in the number of trigger points and painful areas and improvements in mood. In another double-blind study, SAMe was orally administered to a group of 44 patients who suffered from fibromyalgia. Patients given SAMe demonstrated reduction in pain, fatigue, and morning stiffness. Not surprisingly, the SAMe produced no side effects.

SAMe and Migraine Headaches

SAMe is also beneficial in the treatment of migraine headaches. The benefits manifest gradually, and require long-term treatment for therapeutic effectiveness.

Enterically Coated SAMe Tablets for Oral Administration

In order for SAMe to work, it must first get into the bloodstream. Unfortunately, when it is taken orally, gastric acid attacks SAMe and removes its active methyl group. To avoid deactivation in the stomach, one should use enterically coated tablets. Enterically coated SAMe tablets are time-released to pass through the stomach unchanged and break down in the small intestines where they are released for absorption in the intestinal tract. Enterically-coated SAMe tablets should be taken on an empty stomach
to avoid premature breakdown in the stomach.

SAMe and Melatonin Synthesis –

When to Take SAMe

SAMe helps to maintain normal circadian rhythms by donating a methyl group molecule to the enzyme that converts serotonin into melatonin, the body’s primary regulator of circadian rhythms. Significantly, the circadian secretory patterns of SAMe and melatonin are 180 degrees out-of-phase. In other words, SAMe levels are highest during the day and lowest at night, while melatonin levels are lowest during the day and highest at night. In the evening, about 30 minutes before sunset, levels of SAMe increase to their highest level, remain there for about an hour and rapidly fall. As SAMe levels fall, melatonin levels rise. Five hours into the night, melatonin reaches its highest level and SAMe hits its lowest level. Three hours before sunrise, when melatonin levels abruptly fall, SAMe levels start to increase to their daily peak and the pattern repeats. Based on these data, it is probably best to take SAMe during the day and avoid evening doses to complement the body’s natural secretory rhythm of SAMe.

Non-toxic and safe

SAMe is extremely safe and non-toxic. In clinical studies, SAMe is typically compared against placebo and other compounds for benefits and side effects. While SAMe usually produces beneficial effects superior to drugs and other nutrients, it often produces an incidence of side effects that are lower than the placebo!

Dosage Guidelines

Below are dosage ranges of SAMe that have been found to be effective for various conditions. SAMe can cause nausea and gastrointestinal upset in some sensitive people, so we recommend starting with the lower dosage and increasing the dosage as tolerated.


— Four hundred milligrams, three to four times daily. Start at a dosage of 200 milligrams twice daily for the first day. Increase to 400 milligrams twice daily on day three, 400 milligrams three times daily on day ten, and finally to the full dosage of 400 milligrams four times daily after 20 days, if required.


— Start by following the guidelines for depression. After 21 days at a dosage of 1,200 milligrams daily, reduce dosage to a maintenance dosage (minimum dosage required to alleviate symptoms) of two hundred milligrams a day.


— Two hundred milligrams to four hundred milligrams, two times daily.

Liver Disorders

— Two hundred milligrams to four hundred milligrams, two to three times daily.

Migraine Headaches

–Two hundred milligrams to four hundred milligrams, two times daily (Requires long term use of SAMe for maximum effectiveness).


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